The principal objective of the program of research outlined herein is the development of general strategies and methods for the syntheses of selected natural products possessing anticancer activity. During the course of these studies, it will be necessary to invent new synthetic methods and to explore the scope and limitations of existing ones. Specifically, a novel and unified entry to the promising antitumor ansa macrocyles macbecin (NSC 330500) and herbimycin will be developed. The strategy is endowed with sufficient flexibility to allow preparation from advanced, common intermediates of the related macrocyclic lactam geldanamycin, which is an inhibitor of DNA-dependent-RNA polymerase. Macbecin exhibits significant antitumor activity but not antitublinic activity, and geldanamycin is an inhibitor of a reverse transcriptase. One of the methodological challenges of these endeavors will be the design and development of new synthetic methods for the construction of trisubstituted olefins. Tactics for achieving the stereoselective addition of organometallic reagents to lactols will be explored. Finally, new applications of the use of furans and hydropyranones derived therefrom in asymmetric synthesis of acyclic arrays will be developed. Two different synthetic approaches to the anticancer alkaloids lycoricidine, narciclasine, and pancratistatin have been formulated. Hetero Diels-Alder reactions will be exploited for the development of a facile entry to the aminocyclitol subunit in both racemic and optically pure form. Organocuprate chemistry and radical cyclization methodology will then be marshalled as key steps for the construction of the tricyclic ring system. Some new aspects of asymmetric synthesis in hetero Diels-Alder reactions will be explored as will some interesting facets of radical cyclization and organocuprate chemistry. The synthetic approaches to the selected naturally-occurring targets are designed to be sufficiently flexible and efficient so that analogues may be readily prepared for study of structure-activity relationships. Selected compounds will be submitted to C.P. Starks, Inc., the Eli Lilly Company, the Upjohn Company, Abbott Laboratories, and DuPont for screening for biological activity, and compounds having promising anticancer activity will be submitted to the National Cancer Institute for further biological evaluation.